Otitis media is a world-wide disease primarily affecting the pediatric population under the age of 5 years. It is the most common reason for pediatric care visits and antibiotic therapy. Over-prescription and poor- compliance have led to a reduced susceptibility of bacteria to antibiotics and, consequentially, to recurrent and chronic ear diseases. Clearly, there is a compelling need to investigate alternative therapeutic modalities. The middle ear is a large cavity. It makes use of components of the innate immune response to trap bacteria, containing them for elimination by phagocytes. However, these components can also encapsulate bacteria and protect them by immune evasion. We will investigate the efficacy of a formulation for the treatment of otitis media that targets both the innate response of the middle ear to infection and the pathogen. We will first target host containment of bacteria to expose them to treatment. Treatment consists of a potent antimicrobial peptide and a key molecule of the early innate response of the middle ear mucosa to infection. Bacteria will also be treated with an antibiotic/corticosteroid. Bacterial resistance is a world-wide health concern. We believe that our combination of antibiotic and non-antibiotic modalities will be successful in eliminating bacteria in the middle ear, thereby helping to prevent recurrent and chronic infections. Not only is there a need to challenge traditional pharmacologic treatments, but to develop non-traditional methods of administration as well. The conventional method of treating otitis media with oral antibiotics exposes other organs to the treatment, as well as the middle ear. Topical treatment would be ideal in that it would limit treatment to the middle ear and provide a greater concentration of the pharmacologic agent to the infected area. And because the treatment is administered as an eardrop, it can be applied at time of diagnosis, thus ensuring compliance. Like the skin, the tympanic membrane is impermeable to most substances, necessitating a penetration enhancement vehicle. A number of these have been studied, but with limited success. We are using a penetration enhancement vehicle that has been well characterized. It has been shown to pass the epidermis of the skin via pore formation, and so should likely pass the epidermis of the tympanic membrane. Moreover, it is not ototoxic to the sensory-neural structures of the inner ear. Otitis media is world-wide health concern that has broad-reaching medical and socioeconomic challenges. We have designed a drug intended to more effectively eliminate bacteria from the middle ear in the acute stages of otitis media, preventing recurrent and chronic infections. We are likewise investigating its topical transtympanic administration with a penetration enhancement vehicle that is a powerful solvent with potential for use in the treatment of otitis media and other ear diseases.